Humoral autoimmune and alloimmune conditions are mediated by pathogenic antibodies. Some examples of autoimmune diseases include immune neutropenia, myasthenia gravis, multiple sclerosis, lupus and immune thrombocytopenia (ITP).
ITP is primarily a disease of increased peripheral platelet destruction, where most patients develop antibodies that bind to specific platelet membrane glycoproteins. The anti-platelet antibodies effectively opsonize platelets, leading to rapid platelet destruction by cells of the reticulo-endothelial system (e.g., macrophages). Relative marrow failure may contribute to this condition, since studies show that most patients have either normal or diminished platelet production. In general, attempts to treat ITP include suppressing the immune system, and consequently causing an increase in platelet levels.
ITP affects women more frequently than men, and ITP is considered to be an autoimmune disease that is common in children and adults. The incidence is 1 out of 10,000 people. In the US, the incidence of ITP in adults is approximately 66 cases per 1,000,000 per year. An average estimate of the incidence in children is 50 cases per 1,000,000 per year. Internationally, childhood ITP occurs in approximately 10-40 cases per 1,000,000 per year.
This problem is significant because chronic ITP is one of the major blood disorders in both adults and children. It is a source of significant hospitalization and treatment cost at specialized hematological departments in the US and around the world. Each year there are approximately 20,000 new cases in the US, and the cost for ITP care and special therapy is extremely high.
Most children with ITP have a very low platelet count that causes sudden bleeding, with typical symptoms including bruises, small red dots on the skin, nosebleeds and bleeding gums. Although children can sometimes recover with no treatment, many doctors recommend careful observation and mitigation of bleeding and treatment with intravenous infusions of gamma globulin.
Intravenous administration of human immunoglobulin (IVIG) in large amounts has been shown to increase platelet counts in children afflicted with immune ITP, and IVIG has shown to be beneficial as a treatment for several other autoimmune conditions.
Many studies have investigated the mechanisms by which IVIG achieves effects in the treatment of autoimmune diseases. With regard to ITP, early investigations led to the conclusion that IVIG effects are mainly due to blockade of the Fc receptors responsible for phagocytosis of antibody-opsonized platelets. Subsequent studies showed that Fc-depleted IVIG preparations provided increases in platelet counts in some patients with ITP, and recently it was reported that IVIG effects are due to stimulation of FcγRIIb expression on macrophage cells, leading to inhibition of platelet phagocytosis. Such IVIG treatments, however, have substantial side effects and are very costly to develop and administer. Further, other therapies used for the treatment of autoimmune/alloimmune conditions other than IVIG include polyclonal anti-D immunoglobulin, corticosteroids, immuno-suppressants (including chemotherapeutics), cytokines, plasmapheresis, extracorporeal antibody adsorption (e.g., using Prosorba columns), surgical interventions such as splenectomy, and others. However, like IVIG, these therapies are also complicated by incomplete efficacy and high cost.
Recently, it has been proposed to raise anti-human FeRn antibodies in knock-out mice lacking the FcRn gene (Roopenian, 2002, U.S. publication no. 2002/138863). The author argues that high affinity antibodies that bind to the same epitope of FcRn as IgG would competitively inhibit the binding of pathogenic IgG to FcRn and therefore increase clearance. However, no such antibodies were demonstrated and therefore the efficacy of such antibodies is still in question. Moreover, owing to the high affinity of endogenous IgG to FcRn and to the high concentrations of endogenous IgG in blood, it is likely that competitive inhibition of FcRn would require very high doses and therefore may be associated with similar side effects as the current IVIG treatment.
Based on the state of the prior art, there is substantial need for the development of new therapies for autoimmune and alloimmune conditions that do not have the low potency and high cost of IVIG. It is therefore desirable to identify a safer and more effective alternative to IVIG for treatment for autoimmune and alloimmune conditions.